Aortic aneurysms are often silent and deadly, and there is no medical therapy for them. Veterans, especially those who smoke (nicotine), are highly vulnerable to aortic aneurysms and their sequelae such as ruptures and dissections. Thus, understanding the fundamental basis for the disease is central to developing cures that can have a positive impact on health of veterans. Studies in human cohorts show that the non-coding microRNA-204 (miR-204) is downregulated in aortic aneurysmal tissue compared to non-affected tissue. In addition, human population-based studies have shown increased prevalence of aortic aneurysms and risk of their rupture with use of broad-spectrum antibiotics. These antibiotics are widely (and often inappropriately) prescribed in the VA Health System. Antibiotics change the composition of the healthy gut microbiome (dysbiosis). This application will test the hypothesis that gut dysbiosis caused by antibiotics promotes aortic aneurysms via its effect on aortic miR-204 expression. Dedifferentiation of smooth muscle cells from a normal contractile phenotype to a dysfunctional synthetic one, is a core feature in diseases of arterial remodeling, including aortic aneurysms. Synthetic smooth muscle cells preferentially utilize fat over glucose. This application will also explore the hypothesis that downregulation of miR-204 causes switching of aortic smooth muscle cells from a contractile to a dysfunctional synthetic phenotype by stimulating fatty acid utilization. The hypotheses underlying this application are grounded in exciting data showing that aortic miR-204 expression is governed by the gut microbiome ? dysbiosis caused by broad-spectrum antibiotics leads to profound decrease in aortic miR-204 expression. In addition, absence of miR-204 in mice makes them susceptible to Angiotensin II-induced aortic aneurysmal dilatation and upregulates metabolites in the fatty acid oxidation pathway. This application will leverage state-of-the-art molecular tools and genetically modified mice to examine the role of smooth muscle miR-204 in Angiotensin II-induced and nicotine-induced aortic aneurysms. It will determine if antibiotic-induced dysbiosis down-regulates aortic smooth muscle miR-204 and promotes aortic aneurysmal disease, and whether this disease can be rescued by gain-of-function of miR-204. It will explore the role of miR-204 in regulating the plasticity of smooth muscle cells and investigate whether loss of function of miR-204 promotes dedifferentiation of aortic smooth muscle cells in aneurysmal disease. Additionally, using metabolomics and bioenergetic tools, it will uncover the role of miR-204 in regulating smooth muscle cell preference for fuel utilization, and investigate if deficiency of miR-204 in aortic aneurysmal disease increases smooth muscle fatty acid oxidation. Aortic aneurysms are common and represent a significant health burden in veterans. This application offers a unique opportunity to explore how a vascular microRNA regulated by gut bacteria is involved in the pathogenesis of aortic aneurysmal disease and could offer hope for new therapies for veterans who suffer from this disease.